Stribild

1 INDICATIONS AND USAGE STRIBILD ® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older weighing at least 35 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of STRIBILD . STRIBILD is a four-drug combination of elvitegravir, an HIV integrase strand transfer inhibitor (HIV-1 INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir disoproxil fumarate (TDF), both HIV nucleoside analog reverse transcriptase inhibitors (HIV NRTI) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older weighing at least 35 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of STRIBILD. ( 1 , 14 )

Testing: Prior to initiation of STRIBILD, test patients for hepatitis B virus infection. Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, serum phosphorous, estimated serum creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Recommended dosage: One tablet taken once daily with food. Dosage in renal impairment: Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Discontinue in patients with estimated creatinine clearance below 50 mL per minute.

2.1Testing Prior to Initiation and During Treatment

with STRIBILD Prior to initiation of STRIBILD, test patients for hepatitis B virus infection . Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus .

2.2Recommended Dosage

STRIBILD is a four-drug fixed dose combination product containing 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of TDF. The recommended dosage of STRIBILD is one tablet taken orally once daily with food in adults and pediatric patients 12 years of age and older with a body weight at least 35 kg and creatinine clearance greater than or equal to 70 mL per minute .

2.3Dosage Adjustment in Patients with Renal Impairment

Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Because STRIBILD is a fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute during treatment with STRIBILD, as the dose interval adjustment required for emtricitabine and tenofovir disoproxil fumarate (DF) cannot be achieved . No data are available to make dose recommendations for pediatric patients with renal impairment.

2.4Not Recommended in Patients with Severe Hepatic

Impairment STRIBILD is not recommended for use in patients with severe hepatic impairment .

2.5Not Recommended During Pregnancy

STRIBILD is not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters . STRIBILD should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with STRIBILD .

New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering STRIBILD with concurrent or recent use of nephrotoxic drugs. Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. Risk of adverse reactions or loss of virologic response due to drug interactions: The concomitant use of STRIBILD and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of STRIBILD and possible development of resistance; clinically significant adverse reactions from greater exposures of concomitant drugs; or loss of therapeutic effect of concomitant drugs. Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. Immune reconstitution syndrome: May necessitate further evaluation and treatment.

5.1Severe Acute Exacerbation of Hepatitis B

in Patients Coinfected with HIV-1 and HBV All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy . Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued emtricitabine or TDF, two of the components of STRIBILD. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, a component of STRIBILD, and with the use of STRIBILD . In the clinical trials of STRIBILD over 144 weeks, 13 (1.9%) subjects in the STRIBILD group (N=701), 8 (2.3%) subjects in the atazanavir (ATV) + ritonavir (RTV) + TRUVADA ® (emtricitabine 200 mg/TDF 300 mg) group (N=355), and no subjects in the ATRIPLA ® (efavirenz 600 mg/emtricitabine 200 mg/TDF 300 mg) group (N=352) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 8 in the STRIBILD group and 1 in the ATV+RTV+TRUVADA group occurred during the first 48 weeks. Four (0.6%) subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction, leading to discontinuation of STRIBILD during the first 48 weeks of treatment.

Two of the four subjects had renal impairment (i.e., estimated creatinine clearance less than 70 mL per minute) at baseline. The laboratory findings in these 4 subjects improved but did not completely resolve in all subjects upon discontinuation of STRIBILD. Renal replacement therapy was not required for these subjects. One (0.3%) subject who received ATV+RTV+TRUVADA developed laboratory findings consistent with proximal renal tubular dysfunction, leading to discontinuation of ATV+RTV+TRUVADA after Week 96.

STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]) . Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue STRIBILD in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended . Although cobicistat (a component of STRIBILD) may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function , patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety. The emtricitabine and TDF components of STRIBILD are primarily excreted by the kidney. STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute as dose interval adjustment required for emtricitabine and TDF cannot be achieved with the fixed-dose combination tablet .

5.3Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic

acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including TDF and emtricitabine, components of STRIBILD, alone or in combination with other antiretrovirals. Treatment with STRIBILD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.4Risk of Adverse Reactions or Loss of Virologic

Response Due to Drug Interactions The concomitant use of STRIBILD and other drugs may result in known or potentially significant drug interactions, some of which may lead to : Loss of therapeutic effect of STRIBILD and possible development of resistance. Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events, from greater exposures of concomitant drugs metabolized by CYP3A. Loss of therapeutic effect of concomitant drugs that utilize CYP3A to form active metabolites. See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations . Consider the potential for drug interactions prior to and during STRIBILD therapy; review concomitant medications during STRIBILD therapy; and monitor for the adverse reactions associated with the concomitant drugs.

5.5Bone Loss and Mineralization Defects Bone

Mineral Density In clinical trials in HIV-1 infected adults, TDF (a component of STRIBILD) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF. For additional information, and consult the TDF prescribing information. Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted.

Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected pediatric subjects as compared to the control groups.

In all pediatric trials, skeletal growth (height) appeared to be unaffected. For more information, please consult the TDF prescribing information. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for HIV-1 infected adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.

Although the effect of supplementation with calcium and Vitamin D was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained. Mineralization Defects Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF . Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy.

Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF .

5.6Immune Reconstitution Syndrome Immune

reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including STRIBILD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

Coadministration of STRIBILD is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of STRIBILD and possible resistance) are listed below . Alpha 1-adrenoreceptor antagonist: alfuzosin Anticonvulsants: carbamazepine, phenobarbital, phenytoin Antimycobacterial: rifampin Antipsychotics: lurasidone, pimozide Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine Herbal Products: St. John's wort ( Hypericum perforatum ) Lipid-modifying Agents: lomitapide, lovastatin, simvastatin Phosphodiesterase-5 (PDE-5) Inhibitor: sildenafil when administered as Revatio ® for the treatment of pulmonary arterial hypertension Sedative/hypnotics: triazolam, orally administered midazolam Coadministration of STRIBILD is contraindicated with drugs that: Are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious adverse events.

Strongly induce CYP3A, which may lead to lower exposure of one or more components and loss of efficacy of STRIBILD and possible resistance.

8.1Pregnancy Pregnancy Exposure Registry There

is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to STRIBILD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary STRIBILD is not recommended during pregnancy . A literature report evaluating the pharmacokinetics (PK) of antiretrovirals during pregnancy demonstrated substantially lower exposures of elvitegravir and cobicistat in the second and third trimesters . Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage.

However, elvitegravir, cobicistat, emtricitabine, and TDF use during pregnancy have been evaluated in a limited number of individuals as reported to the APR. Available data from the APR show no significant difference in the overall risk of major birth defects for elvitegravir, cobicistat, emtricitabine, or TDF compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) . The rate of miscarriage is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15–20%. In animal studies, no adverse developmental effects were observed when the components of STRIBILD were administered separately during the period of organogenesis at exposures up to 23 and 0.2 times (rats and rabbits, respectively, elvitegravir), 1.8 and 4.3 times (rats and rabbits, respectively, cobicistat), and 60 and 120 times (mice and rabbits, respectively, emtricitabine) the exposure at the recommended daily dose of these components in STRIBILD, and at 14 and 19 times (rats and rabbits, respectively, TDF) the human dose based on body surface area comparisons . Likewise, no adverse developmental effects were seen when elvitegravir or cobicistat was administered to rats through lactation at exposures up to 18 times or 1.2 times, respectively, the exposure at the recommended daily therapeutic dose, and when emtricitabine was administered to mice through lactation at exposures up to approximately 60 times the exposure at the recommended daily therapeutic dose. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 2.7 times the exposure at the recommended daily dosage of STRIBILD. Data Human Data A prospective study, reported in the literature, enrolled 30 pregnant women living with HIV who were receiving elvitegravir and cobicistat-based regimens in the second or third trimesters of pregnancy and through 6 to 12 weeks postpartum to evaluate the pharmacokinetics (PK) of antiretrovirals during pregnancy. Twenty-eight women completed the study through the postpartum period.

Paired pregnancy/postpartum PK data were available from 14 and 24 women for the second and third trimesters, respectively. Exposures of elvitegravir and cobicistat were substantially lower during the second and third trimesters compared to postpartum. The proportion of pregnant women who were virologically suppressed was 77% in the second trimester, 92% in the third trimester, and 76% postpartum.

No correlation was observed between viral suppression and elvitegravir exposure. HIV status was also assessed for infants: 25 were uninfected, 2 had indeterminate status, and no information was available for 3 infants. Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of STRIBILD are compared with a U.S. background major birth defect rate.

Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. Elvitegravir: Based on prospective reports to the APR of exposures to elvitegravir-containing regimens during pregnancy resulting in live births (including over 300 exposed in the first trimester and over 60 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.4% (95% CI: 1.7% to 6.0%) and 1.5% (95% CI: 0% to 7.9%) following first and second/third trimester exposure, respectively, to elvitegravir-containing regimens.

Cobicistat: Based on prospective reports to the APR of exposures to cobicistat-containing regimens during pregnancy resulting in live births (including over 400 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.9% (95% CI: 2.2% to 6.3%) and 1.2% (95% CI: 0.0% to 6.5%) following first and second/third trimester exposure, respectively, to cobicistat-containing regimens. Emtricitabine: Based on prospective reports to the APR of exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including over 3,600 exposed in the first trimester and over 1,400 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.1% to 3.2%) and 2.4% (95% CI: 1.6% to 3.3%) following first and second/third trimester exposure, respectively, to emtricitabine-containing regimens. Tenofovir DF: Based on prospective reports to the APR of exposures to TDF-containing regimens during pregnancy resulting in live births (including over 4,200 exposed in the first trimester and over 1,800 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 2.9%) and 2.4% (95% CI: 1.8% to 3.2%) following first and second/third trimester exposure, respectively, to TDF-containing regimens.

Animal Data Elvitegravir: Elvitegravir was administered orally to pregnant rats (at 0, 300, 1000, and 2000 mg/kg/day), and rabbits (at 0, 50, 150, and 450 mg/kg/day) through organogenesis (on gestation days 7 through 17 and days 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with elvitegravir in rats at exposures (AUC) approximately 23 times higher and in rabbits at approximately 0.2 times higher than human exposures at the recommended daily dose. In a pre- and postnatal developmental study in rats, elvitegravir was administered orally at doses of 0, 300, 1000, and 2000 mg/kg from gestation day 7 to day 20 of lactation.

At doses of 2000 mg/kg/day of elvitegravir, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 18 times the human exposures at the recommended daily dose. Cobicistat: Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, and 125 mg/kg/day on gestation day 6 to 17.

Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.8 times higher than human exposures at the recommended daily dose.

In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 4.3 times higher than human exposures at the recommended daily dose.

In a pre- and postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation day 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.2 times the human exposures at the recommended daily dose.

Emtricitabine: Emtricitabine was administered orally to pregnant mice (at 0, 250, 500, or 1000 mg/kg/day), and rabbits (at 0, 100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study in mice, emtricitabine was administered orally at doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.

Tenofovir DF: Tenofovir DF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of STRIBILD.

The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B in Patients Coinfected with HIV-1 and HBV . New Onset or Worsening Renal Impairment . Lactic Acidosis/Severe Hepatomegaly with Steatosis . Bone Loss and Mineralization Defects . Immune Reconstitution Syndrome . Most common adverse drug reactions to STRIBILD (incidence greater than or equal to 10%, all grades) are nausea and diarrhea. To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in HIV-1 Infected Adult Subjects with No Antiretroviral Treatment History The safety assessment of STRIBILD is based on the Week-144 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103, in antiretroviral treatment-naïve HIV-1 infected adult subjects . A total of 701 subjects received STRIBILD once daily in these two studies. The proportion of subjects who discontinued treatment with STRIBILD, ATRIPLA, or ATV+RTV+TRUVADA due to adverse events, regardless of severity, was 6.0%, 7.4%, and 8.5%, respectively.

Table 1 displays the frequency of adverse reactions greater than or equal to 5% of subjects in any treatment arm. Table 1 Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drugs. (All Grades) Reported in ≥5% of Adult Subjects in Any Treatment Arm in Studies 102 and 103 (Week-144 Analysis) STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 EYE DISORDERS Ocular icterus <1% 0% 13% GASTROINTESTINAL DISORDERS Diarrhea 12% 11% 17% Flatulence 2% <1% 8% Nausea 16% 9% 14% GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 4% 8% 6% HEPATOBILIARY DISORDERS Jaundice 0% <1% 9% NERVOUS SYSTEM DISORDERS Somnolence 1% 7% 1% Headache 7% 4% 6% Dizziness 3% 21% 5% PSYCHIATRIC DISORDERS Insomnia 3% 9% 1% Abnormal dreams 9% 27% 4% SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Rash event includes dermatitis, drug eruption, eczema, pruritus, pruritus generalized, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, and urticaria. 4% 15% 6% See Warnings and Precautions for a discussion of renal adverse reactions from clinical trials experience with STRIBILD. Additional adverse reactions observed with STRIBILD included suicidal ideation and suicide attempt (0.3%), all in subjects with a preexisting history of depression or psychiatric illness. Clinical Trials in Virologically Suppressed HIV-1 Infected Adult Subjects No new adverse reactions to STRIBILD through Week 48 were identified in 584 virologically stably suppressed adult subjects switching to STRIBILD from a regimen containing a RTV-boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI).

In a combined analysis of studies 115 and 121, the frequency of adverse reactions (all grades) was 24% in subjects switching to STRIBILD compared to 6% of subjects in either group who stayed on their baseline antiretroviral regimen, RTV-boosted PI+TRUVADA or NNRTI+TRUVADA. Common adverse reactions that occurred in greater than or equal to 2% of subjects switching to STRIBILD were nausea (4%), flatulence (2%), and headache (2%). The proportion of subjects who discontinued treatment with STRIBILD, the RTV-boosted PI, or the NNRTI due to adverse events was 2%, 3%, and 1%, respectively. Clinical Trials of the Components of STRIBILD in Adult Subjects Emtricitabine and TDF: In addition to the adverse reactions observed with STRIBILD, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or TDF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.

Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving STRIBILD in studies 102 and 103 are presented in Table 2.

Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Adult Subjects Receiving STRIBILD in Studies 102 and 103 (Week-144 Analysis) Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. , For subjects with serum amylase >1.5 × upper limit of normal (ULN), lipase test was also performed. The frequency of increased lipase (Grades 3–4) occurring in STRIBILD (N=69), ATRIPLA (N=40), and ATV+RTV+TRUVADA (N=38) was 17%, 15%, and 24%, respectively. STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 AST (>5.0 × ULN) 3% 6% 6% ALT (>3.0 × ULN) 2% 5% 4% Amylase (>2.0 × ULN) 3% 3% 5% Creatine Kinase (≥10.0 × ULN) 8% 15% 11% Urine RBC (Hematuria) (>75 RBC/HPF) 4% 2% 4% In Study 103, BMD was assessed by DEXA in a nonrandom subset of 120 subjects (STRIBILD group, N=54; ATV+RTV+TRUVADA group, N=66).

Mean percentage decreases in BMD from baseline to Week 144 in the STRIBILD group were comparable to that in the ATV+RTV+TRUVADA group at the lumbar spine (−1.43% versus −3.68%, respectively) and at the hip (−2.83% versus −3.77%, respectively). In studies 102 and 103, bone fractures occurred in 27 subjects (3.9%) in the STRIBILD group, 8 subjects (2.3%) in the ATRIPLA group, and 19 subjects (5.4%) in the ATV+RTV+TRUVADA group. These findings were consistent with data from an earlier 144-week trial of treatment-naïve subjects receiving TDF + lamivudine + efavirenz.

Proteinuria (all grades) occurred in 52% of subjects receiving STRIBILD, 41% of subjects receiving ATRIPLA, and 42% of subjects receiving ATV+RTV+TRUVADA. The cobicistat component of STRIBILD has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In studies 102 and 103, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with STRIBILD, after which levels stabilized. Table 3 displays the mean changes in serum creatinine and eGFR levels at Week 144 and the percentage of subjects with elevations in serum creatinine (all grades).

Table 3 Change from Baseline in Serum Creatinine and eGFR and Incidence of Elevated Serum Creatinine (All Grades) in Studies 102 and 103 at Week 144 STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 Serum Creatinine (mg/dL) Mean change ± standard deviation 0.14 (±0.14) 0.01 (±0.12) 0.09 (±0.15) eGFR by Cockcroft-Gault (mL/minute) −14.0 (±16.6) −1.9 (±17.9) −9.8 (±19.4) Subjects with Elevations in Serum Creatinine (All Grades) (%) 12 2 6 Emtricitabine or TDF: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or TDF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of ALT (M: greater than 215 U per L; F: greater than 170 U per L), alkaline phosphatase (greater than 550 U per L), bilirubin (greater than 2.5 × ULN), serum glucose (less than 40 or greater than 250 mg per dL), glycosuria (greater than or equal to 3+), neutrophils (less than 750 per mm 3 ), fasting cholesterol (greater than 240 mg per dL), and fasting triglycerides (greater than 750 mg per dL). Serum Lipids: In the clinical trials of STRIBILD, a similar percentage of subjects receiving STRIBILD, ATRIPLA, and ATV+RTV+TRUVADA were on lipid-lowering agents at baseline (12%, 12%, and 13%, respectively). While receiving study drug through Week 144, an additional 11% of STRIBILD subjects were started on lipid-lowering agents, compared to 13% of ATRIPLA and 12% of ATV+RTV+TRUVADA subjects.

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 4. Table 4 Lipid Values, Mean Change from Baseline at Week 144 in Adult Subjects Receiving STRIBILD or Comparator in Studies 102 and 103 STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 Baseline Week 144 Baseline Week 144 Baseline Week 144 mg/dL Change The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. mg/dL Change mg/dL Change Total Cholesterol (fasted) 166 [N=675] +17 [N=535] 161 [N=343] +22 [N=262] 168 [N=337] +16 [N=243] HDL-cholesterol (fasted) 43 [N=675] +7 [N=535] 43 [N=343] +9 [N=262] 42 [N=335] +7 [N=242] LDL-cholesterol (fasted) 100 [N=675] +15 [N=535] 97 [N=343] +19 [N=262] 101 [N=337] +18 [N=242] Triglycerides (fasted) 122 [N=675] +12 [N=535] 121 [N=343] +5 [N=262] 132 [N=337] +22 [N=242] Clinical Trials in Pediatric Subjects The safety of STRIBILD in 50 HIV-1 infected, treatment-naïve pediatric subjects aged 12 to less than 18 years and weighing at least 35 kg was evaluated through 48 weeks in an open-label clinical trial (Study 112) . In this study, the safety profile of STRIBILD was similar to that in adults. Twenty-two subjects (44%) had treatment-emergent proteinuria (Grades 1–2).

One subject met laboratory criteria for proximal renal tubulopathy, evidenced by sustained proteinuria and normoglycemic glycosuria beginning at Week 32. The subject continued to receive STRIBILD and was ultimately lost to follow-up. Among the 50 pediatric subjects receiving STRIBILD for 48 weeks, mean BMD increased from baseline to Week 48, +0.68% at the lumbar spine and +0.77% for total body less head.

Mean changes from baseline BMD Z-scores (height-age adjusted) to Week 48 were −0.09 for lumbar spine and −0.12 for total body less head. At Week 48, 7 STRIBILD subjects had significant (greater than or equal to 4%) lumbar spine BMD loss and 2 had significant total body less head BMD loss.

6.2Postmarketing Experience The

following adverse reactions have been identified during post-approval use of TDF. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. No additional postmarketing adverse reactions specific for emtricitabine have been identified. Immune System Disorders allergic reaction, including angioedema Metabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders dyspnea Gastrointestinal Disorders pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT) Skin and Subcutaneous Tissue Disorders rash Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.